All strokes begin with a sudden interruption of blood flow in the brain. But what happens after that, and why neurons continue to lose function and die over several days, remains one of the most important unanswered questions in neuroscience.
A research team led by C. Justin Lee, director of the Center for Memory and Glioscience at the Institute of Basic Science (IBS), collaborated with Professor Seung-jun Ryu of Eulji University to uncover a previously unknown mechanism that causes this delayed brain injury. Their findings show that strokes are caused not only by an initial loss of blood flow, but also by a chain reaction in the brain that unfolds over time.
In the brain, neurons depend on astrocytes, star-shaped supporting cells that help maintain the chemical environment and protect neural circuits. After a stroke, astrocytes quickly respond to injury by forming a structure known as the glial barrier. The glial barrier has long been thought to protect surrounding tissues. But new research shows that this reaction can be harmful.
Researchers found that immediately after a stroke, levels of hydrogen peroxide (H₂O₂), an active oxygen molecule, rise sharply in the affected area. This surge causes astrocytes to undergo metabolic changes and begin producing large amounts of collagen type I, a structural protein rarely found in a healthy brain. As collagen accumulates, it becomes incorporated into the glial barrier, creating a dense environment that actively promotes neuronal cell death rather than preventing it.
To confirm that collagen plays a direct role in this process, the researchers first blocked collagen production by silencing key genes in astrocytes. When collagen synthesis is suppressed, neuronal cell death is significantly reduced, demonstrating that this pathway is not just associated with injury, but is a major driver of injury. Further experiments showed that collagen acts as a signaling molecule, activating receptors on neurons and triggering a slow degenerative process that unfolds over several days.
We have elucidated the mechanism by which reactive oxygen species induce collagen synthesis in astrocytes at the molecular and cellular levels. This discovery provides important clues to understanding the diverse causes of neuronal cell death and could form the basis for developing treatments not only for stroke but also for neurodegenerative diseases such as dementia and Parkinson’s disease. ”
Dr. Boyoung Lee, Research Co-corresponding Author and Scientist/Principal Scientist, Basic Science Research Institute
The researchers then asked whether this harmful cascade could be stopped earlier. They tested a newly developed drug called KDS12025, which does not directly target collagen, but reduces hydrogen peroxide levels and prevents the entire process from being triggered. In a mouse model of stroke, this treatment reduced collagen accumulation, prevented glial barrier formation, preserved neurological function, and restored motor skills.
Most surprisingly, the drug remained effective even when given within two days of stroke onset. This finding is particularly important because current stroke treatments are typically limited to a narrow “prime time” window of just a few hours. The extension of this period from hours to days suggests that brain damage previously thought to be irreversible may still be preventable.
To examine whether these effects could be translated to a more human-like system, the research team applied the same approach to a monkey stroke model. While untreated animals were unable to grasp food due to paralysis, monkeys treated with KDS12025 recovered motor function and succeeded in grasping food in all 10 out of 10 behavioral tests. Treated animals also showed reduced brain damage and improved overall neurological function.
Co-author Professor RYU Seungjun added, “We propose hydrogen peroxide and collagen as new therapeutic targets for stroke. We hope that by demonstrating efficacy not only in cells and small animals but also in non-human primate models, we will significantly reduce the time required for clinical translation and bring new hope to patients.”
These findings suggest that stroke is not just a one-time event, but a progressive biological process driven by interactions between different types of cells in the brain. By identifying hydrogen peroxide-induced collagen production in astrocytes as a key step in this process, this study provides a new framework for understanding how brain injury progresses and how it is stopped.
Beyond stroke, the mechanisms uncovered in this study may have broader implications for neurological diseases that involve oxidative stress and tissue remodeling, including neurodegenerative diseases. The results suggest new therapeutic strategies that intervene not only at the moment of stroke onset, but also during the subsequent critical period when brain cells are still at risk but potentially recoverable.
Corresponding author C. Justin Lee, director of IBS, said, “By establishing a ‘one-stop research system’ that integrates all processes from basic research to drug discovery and preclinical validation, we have succeeded not only in identifying the root cause of stroke, but also in presenting specific treatment strategies.We will continue to pursue basic scientific research that directly benefits humanity and society, as exemplified by KDS12025.”
sauce:
Basic Science Research Institute
Reference magazines:
Lee, J.-H. others (2026) Oxidative stress-induced astrocyte collagen biosynthesis promotes glial barrier formation and neuronal death in ischemic stroke. cell metabolism. DOI: 10.1016/j.cmet.2026.04.001. https://www.sciencedirect.com/science/article/pii/S1550413126001397.
